Hyperlipidemia has been recognized as the major risk factor in causing cardiovascular diseases due to atherosclerosis. Atherosclerosis and other such peripheral vascular diseases affect the quality of life of a large population in the world. The therapy aims to lower the elevated plasma LDL cholesterol, low-density lipoprotein and plasma triglycerides in order to prevent or reduce the risk of occurrence of cardiovascular diseases.
Hypolipidemic agents which are PPAR modulators have been disclosed in WO 91/19702, WO 94/01420, WO 94/13650, WO 95/03038, WO 95/17394, WO 96/04260, WO 96/04261, WO 96/33998, WO 97/25042, WO 97/36579, WO 98/28534, WO 99/08501, WO 99/16758, WO 99/19313, WO99/20614, WO 00/23417, WO 00/23445, WO 00/23451, WO 01/53257. WO 03009841 discloses compounds of the following general formula:

These compounds are reported to be hypolipidemic agents. WO 03009841 also discloses certain salts including the sodium salt of some of the compounds disclosed therein. However, these salts either were difficult to isolate due to rapid degradation or were poorly absorbed limiting their efficacy and possibility of further development or were found to degrade on long term storage thereby also limiting their suitability for further pharmaceutical development. It has surprisingly now been found that certain compounds and their selected salts are effective in further pharmaceutical development and are also efficacious than some of the earlier known salts.
The present invention provides synergistic composition of certain hypolipidemic and hypocholesterolemic compounds of formula (Ia) wherein ‘M+’ represents Calcium, Magnesium, Sodium, Potassium, Zinc and Lithium, preferably Magnesium, in combination with one or more therapeutic agents as described herein after.

In another embodiment the present invention describes compounds of formula (I)

wherein ‘R’ is selected from hydroxy, hydroxyalkyl, acyl, alkoxy, alkylthio, thioalkyl, aryloxy, arylthio and M+ represents Calcium, Magnesium, Sodium, Potassium, Zinc, Lithium, L-Arginine, Tromethamine, L-Lysine, Meglumine, Benethamine, Piperazine, Benzylamine, Dibenzylamine, Dicyclohexylamine, Diethylamine, Diphenylamine, α-naphthylamine, O-phenylenediamine, 1,3-Diaminopropane, (S)-α-naphthylethylamine, (S)-3-methoxyphenylethylamine, (S)-4-methoxyphenylethylamine, (S)-4-chlorophenylethylamine, (S)-4-methylphenylethylamine, Cinchonine, Cinchonidine, (−)-Quinine, Benzathine, Ethanolamine, Diethanol amine, Triethanolamine, imidazole, Diethylamine, Ethylenediamine, Choline, Epolamine, Morpholine 4-(2-hydroxyethyl), N—N-diethylethanolamine, Deanol, Hydrabamine, Betaine, Ammonia, Adamantanamine, L-Adamantanmethylamine & Tritylamine. Many of these salts also shows certain superior pharmaceutical &/or chemical properties.
In a preferred embodiment, ‘R’ represents thioalkyl or alkoxy or hydroxyalkyl group; in a still preferred embodiment, ‘R’ represents —SCH3 or —OCH3 group.
Type 2 diabetes is a chronic and progressive disease arising from a complex pathophysiology involving the dual endocrine defects of insulin resistance and impaired insulin secretion. The treatment of Type 2 diabetes typically begins with diet and exercise, followed by oral antidiabetic monotherapy. For many patients, these regimens do not sufficiently control glycemia during long-term treatment, leading to a requirement for combination therapy within several years following diagnosis. However, co-prescription of two or more oral antidiabetic drugs may result in treatment regimens that are complex and difficult for many patients to follow. Combining two or more oral antidiabetic agents into a single tablet provides a potential means of delivering combination therapy without adding to the complexity of patients daily regimens. Such formulations have been well accepted in other disease indications, such as hypertension (HYZAAR™ which is a combination of losartan potassium and hydrochlorothiazide) and cholesterol lowering (VYTORIN™ which is a combination of simvastatin and ezetimibe). The selection of effective and well-tolerated treatments is a key step in the design of a combination tablet. Moreover, it is essential that the components have complementary mechanisms of action and compatible pharmacokinetic profiles. Examples of marketed combination tablets containing two oral antidiabetic agents include Glucovance™ (Metformin and Glyburide), Avandamet™ (Metformin and Rosiglitazone), Metaglip™ (Metformin and Glipizide), Janumet™ (contains Sitagliptin and Metformin), etc.
Biguanide antihyperglycaemic agents are commonly used in the treatment of NIDDM (or Type II diabetes). 1,1-Dimethylbiguanidine (or Metformin) is an example of a biguanide antihyperglycaemic agent.
Metformin represents the only oral antidiabetic agent proven to reduce the total burden of microvascular and macrovascular diabetic complications and to prolong the lives of Type 2 diabetic patients. Furthermore, metformin treatment is often associated with reductions in body weight in overweight patients and with improvements in lipid profiles in dyslipidemic patients. Metformin hydrochloride is marketed as either immediate-release or extended-release formulations with tablet dosage strengths of 500, 750, 850, and 1000 milligrams. Extended-release formulations of metformin have advantages over immediate-release in terms of affording a more uniform maintenance of blood plasma active drug concentrations and providing better patient compliance by reducing the frequency of administration required.
It has now surprisingly been found that Compound of formula (Ia) in combination with a biguanide antihyperglycaemic agent such as Metformin provides a particularly beneficial effect on glycaemic control with no observed adverse effects; such combination is therefore particularly useful for the treatment of diabetes mellitus, especially Type II diabetes and conditions associated with diabetes mellitus.
Statins (or HMG-CoA reductase inhibitors) are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases and statins are therefore used in the prevention of these diseases. Several statins have been approved for the treatment of cardiovascular diseases including Lovastatin (MEVACOR, U.S. Pat. No. 4,231,938), Simvastatin (ZOCOR; U.S. Pat. No. 4,444,784), Pravastatin sodium salt (PRAVACHOL; U.S. Pat. No. 4,346,227), Fluvastatin sodium salt (LESCOL; U.S. Pat. No. 5,354,772), Atorvastatin calcium salt (LIPITOR; U.S. Pat. No. 5,273,995) and Rosuvastatin calcium (CRESTOR; U.S. RE37314). The above mentioned publications are incorporated herein by reference.
The present invention is also based on the surprising finding that statins can increase the activity of PPAR agonists compound of formula (Ia) and can be used to treat or prevent dyslipidemia and type 2 diabetes and other disorders responsive to PPAR activators or PPAR activation, without increasing the risk for side effects such as rhabdomylosis, fluid retention, edema, or congestive heart failure.
Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a novel class of agents that are being developed for the treatment or improvement in glycemic control in patients with Type 2 diabetes. Specific DPP-4 inhibitors currently in clinical trials for the treatment of Type 2 diabetes include sitagliptin phosphate (MK-0431), vildagliptin (LAF-237), saxagliptin (BMS-47718), alogliptin (X), carmegliptin (X), melogliptin (X), dutogliptin (X), denagliptin (X), linagliptin (X), P93/01 (Prosidion), SYR322 (Takeda), GSK 823093, Roche 0730699, TS021 (Taisho), E3024 (Eisai), and PHX-1149 (Phenomix). For example, oral administration of vildagliptin or sitagliptin to human Type 2 diabetics has been found to reduce fasting glucose and postprandial glucose excursion in association with significantly reduced HbA1, levels. Several reviews on the application of DPP-4 inhibitors for the treatment of Type 2 diabetes, have been published such as H.-U. Demuth, et al., “Type 2 diabetes—Therapy with dipeptidyl peptidase IV inhibitors, Biochim. Biophys. Acta, 1751: 33-44 (2005), K. Augustyns, et al., “Inhibitors of proline-specific dipeptidyl peptidases: DPP IV inhibitors as a novel approach for the treatment of Type 2 diabetes,” Expert Opin. Ther. Patents, 15: 1387-1407 (2005) etc.
DPP-4 inhibitors currently approved or in clinical trials for the treatment of Type 2 diabetes include sitagliptin phosphate, vildagliptin, saxagliptin, alogliptin, carmegliptin, melogliptin, dutogliptin, denagliptin, linagliptin, P93/01 (Prosidion), SYR322 (Takeda), GSK 823093, Roche 0730699, TS021 (Taisho), E3024 (Eisai), PHX-1149 (Phenomix), etc.
Sitagliptin free base and pharmaceutically acceptable salts thereof are disclosed in U.S. Pat. No. 6,699,871 the contents of which are hereby incorporated by reference in their entirety. Crystalline sitagliptin phosphate monohydrate is disclosed in international patent publication WO 2005/0031335.
Vildagliptin is the generic name for (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine. Vildagliptin is specifically disclosed in U.S. Pat. No. 6,166,063, the contents of which are hereby incorporated by reference in their entirety.
Saxagliptin is a methanoprolinenitrile derivative specifically disclosed in U.S. Pat. No. 6,395,767, the contents of which are hereby incorporated by reference in their entirety.
Alogliptin is a DPP-IV inhibitor under investigation for the treatment of type 2 diabetes, specifically disclosed in EP 1586571 the contents of which are hereby incorporated by reference in their entirety.
Linagliptin is a DPP-IV inhibitor approved for the treatment of type 2 diabetes specifically disclosed in U.S. Pat. No. 7,407,955 the contents of which are hereby incorporated by reference in their entirety.
Other DPP-IV inhibitors useful in the formulation of the present invention include, but are not limited to alogliptin, carmegliptin, melogliptin, dutogliptin, and denagliptin.
The present invention is also based on the surprising finding that DPP IV inhibitors can increase the activity of PPAR agonists of formula (Ia) and can be used to treat or prevent dyslipidemia and type 2 diabetes and other disorders responsive to PPAR activators or PPAR activation, without increasing the risk for side effects such as rhabdomylosis, fluid retention, edema, or congestive heart failure.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of diabetic medications indicated only for the treatment of type 2 diabetes. SGLT-2 inhibitors work by reducing the amount of glucose being absorbed in the kidneys so that it is passed out in the urine and also by reducing the amount of glucose in blood. Their use in clinical practice is associated with improved glycaemic control, weight loss and a low risk of hypoglycaemia. Dapagliflozin, Canagliflozin, Empagliflozin are some of the SGLT-2 inhibitors which are either approved or are under clinical trials for the treatment of diabetes and associated disorders.
The present invention is also based on the surprising finding that SGLT-2 inhibitors can increase the activity of PPAR agonist compounds of formula (Ia) and can be used to treat or prevent dyslipidemia and type 2 diabetes and other disorders responsive to PPAR activators or PPAR activation, without increasing the risk for side effects such as rhabdomylosis, fluid retention, edema, or congestive heart failure.
Glucagon-like-peptide-1 agonists or GLP-1 agonists are a class of drugs for the treatment of type 2 diabetes. Glucagon-like peptide-1 (GLP-1) enhances glucose-dependent insulin secretion following its release into the circulation from the gut. GLP-1 receptor agonists enhance glucose-dependent insulin secretion by the pancreatic beta-cell, suppress inappropriately elevated glucagon secretion, and slow gastric emptying. GLP-1 agonists are used for diabetes type 2 combined with other anti-diabetic drugs.
The present invention is also based on the surprising finding that GLP-1 receptor agonists can increase the activity of PPAR agonist compounds of formula (Ia) and can be used to treat or prevent dyslipidemia and type 2 diabetes and other disorders responsive to PPAR activators or PPAR activation, without increasing the risk for side effects such as rhabdomylosis, fluid retention, edema, or congestive heart failure.
The acid of Formula (I) is a thick liquid which is difficult to isolate, purify and develop into a pharmaceutical formulation. It is therefore necessary to isolate the acid in a form that is easy to purify, handle, scale up and develop into suitable pharmaceutical formulation. Conversion into suitable salts represent one such means.
Salts often improve physical and biological characteristics of mother compounds without modifying primary pharmacological activity, based on mechanism of action of the compound. Thus there is a continuing need to obtain new salts of Formula (I) having improved physical and/or chemical properties. The present invention satisfies this need by providing new salts of Formula (I).
In an embodiment, the new salts of Formula (I) provide a new opportunity to improve the performance of the synthesis of the Formula (I) acid in a chemically and chirally pure form. These new salts are produced in solid state, have improved characteristics such as stability, and flowability, and are therefore easy to handle in an industrial scale. This makes these new salts suitable as intermediates for preparing the compound of formula (I) in a chemically and chirally pure form, though some of these salts may not be pharmaceutically useful. Some of these salts can also have superior biological properties over one or more of the known salts of Formula (I).
These salts may be present either in substantially crystalline or amorphous forms or may be present as partially crystalline forms. In a preferred embodiment the salts are present in crystalline form. In another preferred embodiment, the salts are present in an amorphous form. In another embodiment, the salts are present in non-solvated/unsolvated form or in a solvent free form. In another embodiment, the salts are present in solvated/hydrated form.